Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is commonly grouped with other types of orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct, suggesting a unique etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and copy number variation. We propose to elucidate the genetic architecture of CP by performing whole genome sequencing of case-parent trios in a well-phenotyped, multi-ethnic cohort. Further, by integrating these data with existing whole genome sequencing data for cleft lip and palate and other structural birth defects, we will be able to identify common pathways or conditions associated with CP. To accomplish these goals, we have assembled the largest cohort of CP trios in the world, drawn from the resources of our multidisciplinary consortium that brings together expertise on OFCs, sequencing, statistical genetics, and functional validation of risk variants. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.